The present invention relates to novel pyrimidine derivatives or pharmaceutically acceptable salts thereof which possess an excellent anti-secretory activity, pharmaceutical compositions containing same as an active ingredient, their novel intermediates, and processes for the preparation thereof.
For the treatment of peptic ulcer disease, various drugs such as antacid, anticholinergic agent, H2-receptor antagonist and proton pump inhibitor have been used. The advent of omeprazole useful as a proton pump inhibitor has rekindled research activities in this field.
However, it has been pointed out that the proton pump inhibition by omeprazole is irreversible, which may induce side effects. Accordingly, various attempts to develop a reversible proton pump inhibitor are being actively made. For example, European Patent Nos. 322133 and 404322 disclose quinazoline derivatives, European Patent No. 259174 describes quinoline derivatives, and WO 91/18887 offers pyrimidine derivatives, as a reversible proton pump inhibitor. Further, the present inventors have also reported quinazoline derivatives in WO 94/14795 and pyrimidine derivatives in WO 96/05177.
The present inventors have carried out extensive research to develop a reversible proton pump inhibitor with improved efficacy, and as a result have discovered that pyrimidine derivatives having a substituted tetrahydroisoquinoline group at 4-position of the pyrimidine nucleus or substituents at the 2-, 5-, or 6-positioni of the pyrirnidine nucleus exhibit excellent proton pump inhibition effects and possess the ability to attain a reversible proton pump inhibition.
Accordingly, it is a primary object of the present invention to provide novel pyrimidine derivatives having a substituted tetraydroisoquinoline group at 4-position of the pyrimidine nucleus or substituents at the 2-, 5-, or 6-position of the pyrirnidine nucleus, or pharmaceutically acceptable salts thereof.
It is another object of the present invention to provide processes for preparing said compounds.
It is a further object of the present invention to provide pharmaceutical compositions for treating peptic ulcer containing the same as active ingredients. it is still another object of the, invention to provide novel intermediate compounds useful for the preparation of the novel pyrimidine derivatives.
In accordance with on aspect of the present invention, there are provided novel pyrimidine derivatives of formula (I) or pharmaceutically acceptable salts thereof: 
wherein:
when A is piperidin-1-yl or xe2x80x94NHxe2x80x94B, wherein B is C3-C4 alkenyl, C3-C7 cycloalkyl, C1-C3 alkoxyethyl, phenylethyl which may be substituted or unsubstituted, 3-trifluoromethylphenylmethyl, 1-naphthyl-methyl, 4-methylthiazol-2-yl or 4-phenylthiazol-2-yl,
R1 is hydrogen or methyl; and
R2, R3, R4 and R5 are hydrogen; or
when A is a group of formula (II): 
when R1 is hydroxymethyl or C1-C3 alkoxymethyl,
R2, R3, R4, R5 and R6 are hydrogen; and
R7 is hydrogen or halogen; or
when R1 is hydrogen or methyl,
R7 is hydrogen or halogen; and
one or two of R2, R3, R4, R5 and R6 is hydroxy, methoxy, or a group of formula (III): 
wherein Z is C1-C4 alkyl, substituted or unsubstituted C2-C4 alkenyl, cycloalkyl, benzyloxyalkyl, alkoxycarbonylalkyl, morpholinomethyl, piperidinomethyl, 4-substituted-piperazine-methyl, substituted or unsubstituted phenyl, naphthyl, substituted or unsubstituted benzyl, thiopen-2-yl-methyl, 1-substituted-pyrrolidin-2-yl or xe2x80x94CHR8NHR9, wherein R8 is hydrogen, methyl, isopropyl, benzyl, benzyloxymethyl, methylthioethyl, benzyloxy-carbonylmethyl, carbamoylmethyl, carbamoylethyl, or 1-benzyl imdazol-4-ylmethyl and R9 is hydrogen or t-butoxycarbonyl; and the others are hydrogen or methyl.
Among the compounds of formula (I), preferred are the compounds of the following formula (I-1): 
wherein R1 is hydrogen or methyl; and Axe2x80x2 is piperidin-1-yl or xe2x80x94NHxe2x80x94B, wherein B is C3-C4 alkyl, C3-C4 alkenyl, C3-C7 cycloalkyl, C1-C3 alkoxyethyl, phenylethyl which may be substituted or unsubstituted, 3-trifluoromethyl phenylmethyl, 1-naphthylmethyl, 4-methylthiazol-2-yl or 4-phenylthiazol-2-yl.
Among the compounds of the formula (I), also preferred compounds are the compounds of the following formula (I-2): 
wherein R1 is hydrogen or methyl; R7 is hydrogen or halogen; one or two of R2xe2x80x2, R3xe2x80x2, R4xe2x80x2, R5xe2x80x2 and R6xe2x80x2 is hydroxy or methoxy and the others are hydrogen or methyl.
Similarly preferred compounds are those of the following formula (I-3) 
wherein R1 is hydrogen or methyl; R7 is hydrogen or halogen; one or two of R2xe2x80x3, R3xe2x80x3, R4xe2x80x3, R5xe2x80x3 and R6xe2x80x3 is a group of formula (III): 
wherein Z is C1-C4 alkyl, substituted or unsbstituted C1-C4 alkenyl, C3-C6 cycloalkyl, benzyloxyalkyl, alkoxycarbonylalkyl, morpholinomethyl, piperidinomethyl, 4-substituted-piperazinomethyl, substituted or unsubstituted phenyl, naphthyl, substituted or unsubstituted benzyl, thiophen-2-yl-methyl, 1-substituted-pyrrolidin-2-yl or xe2x80x94CHR8NHR9, wherein R8 is hydrogen, methyl, isopropyl, benzyl, benzyloxymethyl, methylthioethyl, benzyloxycarbonylmethyl, carbamoylmethyl, carbamoylethyl, or 1-benzyl imdazol-4-ylmethyl and R9 is hydrogen or t-butoxycarbonyl; and
the others are hydrogen or methyl.
Similarly preferred compounds are those of the following formula (I-4) 
wherein R1 is hydroxymethyl or C1-C3 alkoxymethyl; and R7 is hydrogen or halogen.
The pyrimidine derivatives of formula (I) in the present invention may exist in the form of an optical isomer, (R) or (S), or a mixture thereof. Both types of the isomeric compounds are found to exhibit excellent anti-secretory activity.
The compounds of the formula (I-1), (I-2), (I-3), and (I-4) may be prepared in accordance with the following methods.
The compound of formula (I-1a) may be prepared by reacting the compound (IV) with Axe2x80x3H in accordance with Scheme 1 described below. 
wherein R1 is hydrogen or methyl; and Axe2x80x3 is piperidin-1-yl or xe2x80x94NHxe2x80x94B, wherein B is C3-C4 alkyl, C3-C4 alkenyl, C3-C7 cycloalkyl, C1-C3 alkoxyethyl, phenylethyl which may be substituted or unsubstituted, 3-trifluoromethylphenylmethyl, or 1-naphthylmethyl.
In the process of Scheme 1, the compound of formula (IV) may be prepared by the same method as described in WO96/05177. The compound of Axe2x80x3H is commercially available (for example, from Aldrich Co. in U.S.A.).
As shown in Scheme 1, the pyrimidine compounds (IV) are reacted with Axe2x80x3H in the presence of an appropriate solvent and a base for 2 to 5 hours to give the compounds of formula (I-1a). Suitable solvents for this reaction may include dimethylformamide, p-dioxane, dimethylsulfoxide, and propyleneglycol. Suitable base for this reaction may include triethylamine, N,N-dimethylaniline, and pyridine. The reaction temperature preferably ranges from 80xc2x0 C. to 140xc2x0 C.
The compound of formula (I-1b) may be prepared by a process which comprises: chlorinating the compound of formula (V) to give a compound of formula (VI); and reacting the compound of formula (VI) with 1-R1-1,2,3,4-tetrahydroisoquinoline in accordance with Scheme 2 described below. 
wherein R1 is hydrogen or methyl; and R10 is methyl or phenyl.
In the process of Scheme 2, the compound of formula (V) may be prepared by using a known process [see, e.g., J. Med. Chem., 33, 543, (1990); and J. Heterocyclic. Chem., 28, 231 (1991)].
The compound of formula (V) is chlorinated with chlorinating agent, e.g. phosphorous oxychloride, to give a compound of formula (VI). And then the compound of formula (VI) is reacted with 1-R1-1,2,3,4-tetrahydroisoquinoline to give compounds of formula (I-1b).
The compound of formula (I-2a) may be prepared by reacting the compound (VII) with a compound of formula (VIII) in accordance with Scheme 3 described below. 
wherein R1, R2xe2x80x2, R3xe2x80x2, R5xe2x80x2, R6xe2x80x2 and R7 are the same as defined in formula (I-2); and R4xe2x80x2xe2x80x3 is hydrogen or methyl.
In Scheme 3, the reaction may be accomplished under same conditions, e.g., solvent, base, reaction time, and temperature, as those of Scheme 1. And also, a compound of formula (I-2a) wherein R5xe2x80x2 is hydroxy may be prepared by the demethylation of the corresponding compound of formula (I-2a) wherein R5xe2x80x2 is methoxy.
In the process of Scheme 3, the compound of formula (VII) may be prepared in accordance with Scheme 4. 
wherein R1, R2xe2x80x2, R3xe2x80x2, R4xe2x80x2xe2x80x3 and R5xe2x80x2 are the same as defined in the above.
In the process of Scheme 4, the compounds of formula (IX) and (XI) may be prepared by using a known process [see, e.g., J. Heterocyclic. Chem., 28, 231 (1991); Org. Synth., Coll. Vol., IV, 638, (1990); and European Patent No. 230,871].
The compound of formula (IX) is chlorinated with chlorinating agent, e.g. phosphorous oxychloride, to give a compound of formula (X). And then the compound of formula (X) is reacted with a compound of formula (XI) to give compounds of formula (VII). In the process of Scheme 4, the compound of formula (VII) wherein R5xe2x80x2 is hydroxy is prepared by the demethylation of the corresponding compound of formula (VII) wherein R5xe2x80x2 is methoxy.
As shown in Scheme 4, the pyrimidine compounds (X) are reacted with a compound of formula (XI) in the presence of an appropriate solvent and a base for 1 to 24 hours to give the compounds of formula (VII). Suitable solvents for this reaction may include dichloromethane, acetone, acetonitrile, and dimethylformarnmide. Suitable base for this reaction may include triethylamine, N,N-dimethylaniline, and pyridine. The reaction temperature preferably ranges from room temperature to 100xc2x0 C.
The compounds of formula (VII) prepared as above are novel and useful as intermidiates for the preparation of the pyrimidine compounds of formula (I-2a). Therefore, the present invention encompasses, within its scope, the novel compounds of formula (VII) and process for the preparation thereof.
The compound of formula (I-2b) may be prepared from the compound of formula (XII) in accordance with Scheme 5-1 and 5-2 described below. 
wherein R1 and R7 are the same as defined in formula (I-2); R2xe2x80x2xe2x80x3, R3xe2x80x2xe2x80x3, R5xe2x80x2xe2x80x3 and R6xe2x80x2xe2x80x3 are hydrogen or methyl, or one of R2xe2x80x2xe2x80x3, R3xe2x80x2xe2x80x3, R5xe2x80x2xe2x80x3 and R6xe2x80x2xe2x80x3 is hydroxy or methoxy.
The compound of formula (XII) may be prepared by the same method as described in WO96/05177 or WO97/42186.
As shown in Scheme 5-1, the pyrimidine compound (XII) is reacted with p-formaldehyde in formalin solution for 24 hours to give the compounds of formula (I-2ba). The reaction temperature preferably ranges from 20xc2x0 C. to 150xc2x0 C. And also, in Scheme 5-2, the pyrimidine compound (XII) is reacted with chloromethyl methyl ether in a sealed tube to give the compounds of formula (I-2bb).
The compound of formula (I-3) may be prepared by reacting the compound (XIII) with a compound of formula (XIV) in accordance with 
wherein R1, R2xe2x80x3, R3xe2x80x3, R4xe2x80x3, R5xe2x80x3, R6xe2x80x3, R7 and Z are the same as defined in formula (I-3); one or two of R2xe2x80x3xe2x80x3, R3xe2x80x3xe2x80x3, R4xe2x80x3xe2x80x3, R5xe2x80x3xe2x80x3 and R6xe2x80x3xe2x80x3 is hydroxy and the others are hydrogen ; and X is halogen or hydroxy.
When X is halogen in Scheme 6, the pyrimidine compounds (XIII) are reacted with a compound of formula (XIV) in the presence of an appropriate solvent and a base for 3 to 24 hours to give the compounds of formula (I-3). Suitable solvents for this reaction may include dimethylformamide and dichloromethane. Suitable base for this reaction may include triethylamine and pyridine. The reaction temperature preferably ranges from 0xc2x0 C. to 50xc2x0 C.
When X is hydroxy in Scheme 6, the pyrimidine compounds (XIII) are reacted with a compound of formula (XIV) in the presence of an appropriate solvent and a coupling agent for 3 to 24 hours to give the compounds of formula (I-3). Suitable solvents for this reaction may include dimethylformamide and dichloromethane. Suitable coupling agents for this reaction may include 1-hydroxybenzotriazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide and triethylamine. The reaction temperature preferably ranges from 0xc2x0 C. to 50xc2x0 C.
The compound of formula (I-4) may be prepared by reacting the compound (XV) with a compound of formula (XVI) in accordance with Scheme 7 described below. 
wherein R1 is hydroxymethyl or C1-C3 alkoxymethyl; and R7 is hydrogen or halogen.
In Scheme 7, the reaction may be accomplished under same conditions, e.g., solvent, base, reaction time, and temperature, as those of Scheme 1.
The compounds of the present invention may be administered, either orally or intraperitoneally, in an effective amount ranging from 0.1 to 500 mg/kg, preferably from 1.0 to 100 mg/kg, into a subject patient per day.
The present invention further includes, within its scope, pharmaceutically acceptable salts of the compounds of formula (I). The non-toxic salts which fall within the scope of the present invention may include inorganic acid salts such as hydrochloride, sulfate, phosphate and nitrate, and organic acid salts such as tartrate, fumarate, citrate, mesylate and acetate.
The pharmaceutically acceptable salts may be prepared in accordance with a known method, e.g., by reacting the compounds of formula (I) with the acids mentioned above in the presence of a solvent, e.g., ethyl alcohol, dichloromethane, ethyl acetate and diethyl ether.
The present invention also includes within its scope pharmaceutical compositions comprising one or more of the inventive compounds as an active ingredient, in association with a pharmaceutically acceptable carrier, excipient and/or other additives, if necessary. The active ingredient present in the composition may range from 0.1% to 99.9% by weight thereof.
The following Examples are given for the purpose of illustration only, and are not intended to limit the scope of the invention. 2-Chloro-5,6-dimethyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine and 2-chloro-5,6-dimethyl-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine were prepared by the same method as described in WO96/05177.
Step 1: N-(3-methoxyphenylethyl)acetamide
3-methoxyphenethylamine(50 g, 0.33 mol) was dissolved in a soultion of water(130 ml), dichloromethane(210 ml) and sodium hydroxide(17.6 g). Acetyl chloride(25.9 ml, 0.36 mol) was added dropwise at a room temperature to the mixture solution, which was then stirred for 1 hour. The separated dichloromethane layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure to give 63.6 g of the titled compound.
Step 2: 6-methoxy-1-methyl-3,4-dihydroisoquinoline
A mixture soultion of polyphosphoric acid (61.4 ml, 0.66 mol) and phosphorouspentoxide(28.0 g, 0.2 mol) was heated to 90xc2x0 C. N-(3-methoxyphenylethyl) acetamide (63.6 g, 0.33 mol) was added to the mixture solution and then stirred for 2 hours at 110xc2x0 C. The reaction mixture was poured into ice water, adjusted to alkali with potassium hydroxide, and then extracted with ethyl ether. The extract was dried over anhydrous magnesium sulfate and concentrated under a reduces pressure. The resulting residue was purified by a silica gel column chromatography, using a solution of methanol and dichloromethane (1:20) as a eluent, to give 54.0 g of the titled compound.
Step 3: 6-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline
6-methoxy-1-methyl-3,4-dihydroisoquinoline (54.0 g, 0.31 mmol) was added to a suspension of sodium borohydride(5.8 g, 138 mmol) in ethanol. The mixture solution was stirred for 1 hour at a room temperature, cooled to below 5xc2x0 C., acidified with diluted hydrochloric acid, adjusted to alkali with sodium hydroxide solution, and then extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure to give 45.4 g of the titled compound.
Step 1: N-(4-acetoxyphenylethyl)acetamide
The mixture solution of 4-hydroxyphenethylamine(6.86 g, 50 mmol), triethylamine(13.9 ml, 0.1 mol) and dichloromethane(50 ml) was cooled to 0xc2x0 C. Acetylchloride(7.1 ml, 0.1 mol) was added dropwise to the mixture solution, which was then stirred for 2 hours at a room temperature, washed with 4N-hydrochloric acid, dried over anhydrous magnesium sulfate, and then concentrated to give 8.6 g of the titled compound.
Step 2: N-(4-hydroxyphenylethyl)acetamide
A solution of sodium hydroxide(2.3 g, 58 mmol) in water(20 ml) was cooled to 0xc2x0 C. A solution of N-(4-acetoxyphenylethyl)acetamide(6.4 g, 29 mmol) in methanol(40 ml) was added dropwise to the soultion, stirred for 10 minutes, adjusted to pH 1 with hydrochloric acid, and then extracted 3 times with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated. The resulting oily residue was solidified with ethyl ether, filtered, and dried to give 4.4 g of the titled compound.
Step 3: N-(4-methoxyphenylethyl)acetamide
Potassium carbonate (3.5 g, 25.5 mol) and iodomethane(2.0 ml, 31.9 mmol) was added to a solution of N-(4-hydroxyphenylethyl)acetamide (4.4 g, 24.6 mmol) in ethanol(2.4 ml), which was then refluxed for 12 hours. The resulting solid was filtered and washed with ethanol. The filtrate was concentrated to give oily residue, which was diluted with ethyl acetate and washed with water. The separated organic layer was concentrated and the resulting solid was suspended in ethylether, filtered, and dried to give 2.9 g of the titled compound.
Step 4: 7-methoxy-1-methyl-1,2,3,4-tetrahydroisoquinoline
The same procedures as in Step 2 and 3 of Preparation 1-1 were repeated using N-(4-methoxyphenylethyl)acetamide (2.9 g, 14.9 mmol) to afford 0.96 g of the titled compound.
The same procedures as in Preparation 1-1 were repeated using 2-methoxyphenethylamine(5 ml, 34.16 mmol) to afford 6.45 g of the titled compound.
The same procedures as in Preparation 1-1 were repeated using 4,5-dimethoxyphenethylamine(5.0 g, 27.6 mmol) to afford 2.65 g of the titled compound.
Step 1: Preparation of methoxyacetic acid
A mixture solution of methoxyacetonitrile(10 g, 0.14 mole) and conc. hydrochloric acid was stirred for 30 minutes, then refluxed for another 30 minutes, cooled to room temperature, diluted with water, extracted with diethyl ether. The ether solution was separated, dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford 8.3 g of titled compound.
Step 2: Preparation of N-phenylethylmethoxyacetamide
Phenethylamine(11.6 ml, 92.1 mmol) was added dropwise to a solution of dicyclohexylcarbodiimide(19 g, 92.1 mmol), methoxyacetic acid(8.3 g, 92.1 mmol) in dichloromethane(50 ml) at room temperature. After addition was completed, the reaction mixture was stirred for 1 hour at room temperature and the resulting solid was filtered. The filtrate was washed with aqueous hydrochloric acid solution, and the organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure to afford 8.15 g of the titled compound.
Step 3: Preparation of 1-methoxymethyl-1,2,3,4-tetrahydroisoquinoline
The same procedures as in Step 2 and 3 of Preparation 1-1 were repeated using N-phenylethylmethoxyacetamide(8.1 g, 41.9 mmol) to afford 2.6 g of the titled compound.
Step 1: Ethyl 2-methyl-3-oxo-4-methoxybutyrate
Zinc(18.1 ml, 275 mmol), methoxyacetonitrile(13.7 ml, 185 mmol), benzene (180 ml) and a catalytic amount of mercuric chloride were heated to reflux. A solution of ethyl 2-bromopropionate(35.9 ml, 275 mmol) in benzene(30 ml) was added dropwise, then reflux continued for further a hour, and cooled to a room temperature. 10% Aqueous sulfuric acid solution (325 ml) was added, and the organic layer was separated. The aqueous layer was further extracted with ethyl ether and the combined organic layers washed with water and aqueous sodium bicarbonate solution, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 29.3 g of the titled compound.
Step 2: 2-amino-4-hydroxy-6-methoxymethyl-5-methylpyrimidine
Ethyl 2-methyl-3-oxo4-methoxybutyrate(10.5 g, 60 mmol) was added slowly to a suspension of sodium methoxide (6.5 g, 120 mmol) in dimethylformamide(10 ml) while maintaining the reaction temperature under 20xc2x0 C. A solution of guanidine(5.7 g, 60 mmol) in ethanol was added to a reaction mixture, which was then refluxed for 5 hours, cooled to a room temperature, and neutralized with conc. sulfuric acid. The resulting solid was filtered and dried to give 2.7 g of the titled compound.
Step 3: 2,4-dihydroxy-6-methoxymethyl-5-methylpyrimidine
2-amino-4-hydroxy-6-methoxymethyl-5-methylpyrimidine (2.7 g, 16 mmol) was added to 20% aqueous hydrochloric acid solution (7 ml), and heated to 70xc2x0 C. A solution of sodium nitrite (2.3 g, 33.3 mmol) in water was added dropwise to a reaction mixture while maintaining the reaction temperature under 70xc2x0 C. The reaction mixture was cooled to a room temperature. The resulting solid was filtered and dried to give 1.5 g of the titled compound.
Step 4: 2,4-dichloro-6-methoxymethyl-5-methylpyrimidine
A mixture solution of 2,4-dihydroxy-6-methoxymethyl-5-methyl pyrimidine (1.5 g, 8.8 mmol), phosphorous oxychloride(7ml) and N,N-dimethylaniline (0.9 ml) was refluxed for 3 hours, cooled to a room temperature, and then poured into ice water. The aqueous layer was extracted with dichloromethane. The resulting organic layer was dried, concentrated, and purified by a silica gel column chromatography to give 1.3 g of the titled compound.
Step 1: ethyl 4-morpholineacetate
Morpholine(1.65 ml, 18.9 mmol) was added dropwise to a soultion of ethyl bromoacetate(1 ml, 9.0 mmol) in benzene (9 ml). The reaction mixture was stirred for 2 hours at a room temperature, diluted with ethyl ether, and washed with saturated NaCl solution. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure to give 1.11 g of the titled compound as an oil. (Yield 71.2%)
NMR(CDCl3): 1.3(t, 3H), 2.6(t, 4H), 3.2(s, 2H), 3.8(t, 4H), 4.2(q, 2H).
Step 2: 4-Morpholineacetic acid hydrochloride
Ethyl 4-morpholinoacetate (1.1 g, 6.3 mmol) was added to 3M hydrochloric acid solution (35 ml), refluxed for 2 hours, stirred for 1 day at a room temperature, and then concentrated under a reduced pressure. The resulting residue was dissolved in methanol and reconcentrated. The resulting solid was suspended in ethylether, filtered and dried under a reduced pressure to give 1.05 g of the titled compound. (Yield 91.7%)
NMR (DMSO-d6): 3.3(s, 4H), 3.9(s, 4H), 4.2(s, 2H).
Step 1: ethyl 4-benzylpiperazineacetate
4-Benzylpiperazine(3.3 ml, 18.9 mmol) was added to a solution of ethyl bromoacetate(1 ml, 9.0 mmol) in benzene(9 ml), which was then stirred for 2 hours at a room temperature, diluted with ethyl ether, and washed with saturated NaCl solution. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2.38 g of the titled compound. (Yield 100%).
NMR(CDCl3): 1.3(t, 3H), 2.6(t, 8H), 3.2(s, 2H), 3.6(s, 2H), 4.2(q, 2H), 7.3(m, 5H).
Step 2: 4-benzylpiperazineacetic acid dihydrochloride
Ethyl 4-benzylpiperazineacetate (2.38 g, 9.0 mmol) was added to 3M hydrochloric acid solution(12 ml), refluxed for 2 hours, stirred for 1 day at a room temperature, and then concentrated under reduced pressure. The resulting residue was dissolved in methanol and reconcentrated. The resulting solid was suspended in ethyl ether, filtered and dried under a reduced pressure to give 2.14 g of the titled compound. (Yield 77.4%)
NMR(D2O): 3.3(s, 8H), 3.7(s, 2H), 4.0(s, 2H), 7.1(s, 5H).
Step 1:ethyl 1-piperidineacetate
Piperidine(1.87 ml, 18.9 mmol) was added dropwise to a solution of ethyl bromoacetate(1 ml, 9.0 mmol) in benzene(9 ml), stirred for 2 hours at a room temperature, diluted with ethyl ether, washed with saturated NaCl solution. The separated organic layer was dried over anhydrous sodium sulfate and concentrated under a reduced pressure to give 1.26 g of the titled compound. (Yield 81.8%)
NMR(CDCl3): 1.3(t, 3H), 1.5(m, 2H), 1.7(m, 4H), 2.5(t, 4H), 3.2(s, 2H), 4.2(q, 2H).
Step 2: 1-piperidineacetic acid hydrochloride
Ethyl 1-piperidineacetate (1.26 g, 7.4 mmol) was added to 3M hydrochloric acid solution (12 ml), which was then refluxed for 2 hours, stirred for 1 day at a room temperature, then concentrated under a reduced pressure. The resulting residue was dissolved in methanol and reconcentrated. The resulting solid was suspended in ethyl ether, filtered and dried under a reduced pressure to give 0.87 g of the titled compound. (Yield 65.3%). NMR(D2O): 1.0(m, 2H), 1.4(m, 4H), 2.5(m, 2H), 3.1(m, 2H), 3.5(s, 2H).